Adverse reactions to pharmaceutical drugs cause significant morbidity and mortality. Further, when the rate or severity of the adverse reactions causes the withdrawal of a pharmaceutical drug from the market, adverse reactions also cause considerable financial losses to pharmaceutical companies.
A large portion of endobiotics and xenobiotics, including many classes of pharmaceutical drugs, is metabolized by cytochrome p450 super family of enzymes present in human liver tissue. Cytochrome P450 2D6 (CYP2D6) is an isoenzyme of the cytochrome p450 super family and is responsible for the metabolism of many pharmaceutical drugs in commonly prescribed drug classes such as antiarrhythmics, β-receptor blockers, neuroleptics, selective serotonin reuptake inhibitors and antidepressants. Examples of pharmaceutical drugs metabolized by CYP2D6 include amitriptyline, codeine, desipramine, haloperidol, metopropol, tamoxifen and timolol.
There is considerable genetic polymorphism in CYP2D6. Polymorphic variants of CYP2D6 can result in altered metabolism of pharmaceutical drugs due to impaired CYP2D6 function. The altered metabolism can be increased metabolism, decreased metabolism or a shift in the metabolic ratio of enantiomeric forms of a pharmaceutical drug in a mixture of enantiomers. The rate of altered pharmaceutical drugs metabolism due to polymorphic variants of CYP2D6 has been estimated at 7% of Caucasian Americans, 2% of African American and 1% of Asian Americans. However, the true rate of altered pharmaceutical drugs metabolism due to polymorphic variants of CYP2D6 and the distribution of CYP2D6 variants remains poorly understood, especially in individuals of non-northern European descent. Further, there remains large numbers of CYP2D6 variants that are, as yet, uncharacterized.
Due to time and cost limitations, phenotypic drug response variation due to the presence of CYP2D6 variants is not adequately characterized during clinical trials of pharmaceutical drugs, but is only fully characterized once the pharmaceutical drug is used by the general population. There is currently no adequate method of screening a population prior to administration of pharmaceutical drugs in the general population to identify CYP2D6 variants in the population predictive of phenotypes likely to result in adverse reactions.
Therefore, there is a need for a method of screening a population to identify CYP2D6 variants in the population. Further, there is a need for a method of predicting adverse reactions to a pharmaceutical drug that is metabolized by the Cytochrome p450 isoenzyme CYP2D6. Additionally, there is a need to identify all variants of the Cytochrome p450 isoenzyme CYP2D6 that cause altered pharmaceutical drugs metabolism.